The present invention relates to a process for producing ceramics, more specifically relates to a process for producing porous ceramics suitable for use as a bone filler or a DDS carrier. The present invention further relates to composite spherical-shape ceramics suitable for use as a medical or dental bone filler or bone cement or other bioceramic material or various resorbable carriers etc.
In the past, as ceramics having superior biocompatibility, in the field of bone fillers and bone cement, calcium phosphate has been broadly used. The forms at the time of use have mostly been splinter-powder (break to powder), blocks, porous substances, self-setting cements, etc. In particular, in bone fillers, some splinter-powder (break to powder) and blocks have been commercialized.
As an example of application of calcium phosphate, recently attention has been made to the use for DDS carriers. For example, Japanese Unexamined Patent Publication (Kokai) No. 60-106459 discloses a process for producing a sustained drug release type carrier comprising coating combustible beads with calcium phosphate and then sintering them to cause the combustible beads to burn away and leave hollow beads of calcium phosphate, then filling a drug into the hollow portions. Further, Japanese Unexamined Patent Publication (Kokai) No. 59-101145 discloses a process for producing a carrier having a similar effect by impregnating a drug into porous calcium phosphate having open pores.
However, in the above processes, the production steps, such as the injection of the drug into the hollow beads, becomes complicated. Further, it is difficult to control the rate of sustained release of the drug. In the latter process as well, similarly there is a concern over problems such as the complexity of the production steps and the difficulty of control of the rate of sustained release.
On the other hand, spherical-shape calcium phosphate is used as a column filler for liquid chromatography. The general production process is a spray drying granulation method. The spray drying granulation method is generally used for the production of particles having a particle size of 100 xcexcm or less. An extremely large-sized apparatus is required when producing larger particles. Further, as a process for producing spherical-shape calcium phosphate having a size of 100 xcexcm or more, Japanese Unexamined Patent Publication (Kokai) No. 64-75030 discloses a process comprising injecting a ceramics slurry into an oil phase to form a water-in-oil emulsion, then injecting this again into a water phase to solidify the oil phase, followed by sintering to burn off the oil phase, whereby spherical-shape calcium phosphate is obtained.
However, for use as a bone filler, particles having a size of 100 xcexcm or more are desirable. Capital investment is required for producing this by the spray drying granulation method, and therefore, the costs are increased. Further, in the process disclosed in Japanese Unexamined Patent Publication (Kokai) No. 64-75030, production steps for adjusting the oil phase etc. become necessary, and therefore, there are again concerns of increased cost.
An application for DDS requires a superior drug carrying property, biocompatibility, sustained drug release, and biodegrarative. Calcium phosphate is superior in biocompatibility and resorption in the living body or organism. In the past, considerable research went into its application for DDS, but nothing has been commercialized yet. One of the reasons is that, since it is ceramics, it is hard to process. Porosity has to be imparted in order to carry a drug, but it is difficult to change conditions such as the size, strength, distribution of pores, etc. Further, from the viewpoint of the rate of filling in the diseased location or operability, it is desirable that DDS carriers and bone fillers be spherical. Since it is extremely difficult to process ceramics into spheres, this has not yet been commercialized.
Spherical-shape particles have applications in a broad range of fields such as processing powders and carrying catalysts, so that the spherical-shape particles which can be supplied to these fields, it is particularly preferable or sought to produce them in a manner enabling the particle size to be changed in depending upon the order and to enable the particles themselves to functionally carry various substances.
In the medical field, the properties of the particles themselves have come under focus along with the development of drug delivery systems which use particles to carry a drug and effectively release the drug at the desired location in the organism.
Further, in biomaterials as well, calcium phosphate is being broadly used in the fields of bone fillers and bone cement as ceramics superior in biocompatibility. The shapes at the time of use are mostly splinter-powder (break to power), blocks, porous substances, self-setting cement, etc. In particular, in bone fillers, some splinter-powder (break to powder) or blocks have been commercialized.
Japanese Unexamined Patent Publication (Kokai) Nos. 3-131580 and 1-314572 disclose processes of preparation of a porous block of calcium phosphate ceramics. In these processes, it is necessary to shape the block at the time of surgery to match the shape of the bone loss. Further, the implanted block member is often scattered or ejected from the organism before the fusion with the newly grown bone.
To overcome this problem, that is, to cause the granules to fix with each other, Japanese Unexamined Patent Publication (Kokai) Nos. 60-256460 and 60-256461 attempt to use a fibrin paste as a glue. However, a fibrin paste is produced from human blood, therefore had the risk of infection by hepatitis, AIDS, etc.
Further, Japanese Unexamined Patent Publication (Kokai) No. 59-88351 and No. 59-182263 disclose processes for producing a bone repair cement having xcex1-tricalcium phosphate or tetracalcium phosphate as its main ingredient. In these processes, the cement cures at the bone loss portion, then fixes to it densely, so osteoblasts and other tissue and cells will not enter the inside of the filler such as with a porous block. Therefore, the bone substitution ability of a calcium phosphate porous block is superior.
The conventional granular bone filler or porous calcium phosphate block often scatters before fusion with the newly grown bone when implanted in a bone loss portion. Further, the bone cement is inferior in bone substitution capability compared with a porous calcium phosphate bone filler due to the fact that it fixes densely after curing. Therefore, a granular bone filler or porous calcium phosphate block capable of achieving anchoring or preventing scattering at the bone loss portion is preferred. No bone filler having both the functions of a bone filler and bone cement has yet been commercialized.
Accordingly, an object of the present invention is to provide a technique for easily processing a hard-to-process calcium phosphate ceramics into a spherical shape, whereby an effective means of treatment of cancer or bone tumors by impregnation of a drug and administration to the diseased portion is provided, since the spherical-shape ceramics has pores and a resorption in the organism optimal for DDS.
Another object of the present invention is to enable the simple and easy production of spherical-shape ceramics having a functional composite layer having a porous inside and having an outer periphery with different physical properties from the inside, more particularly, to provide a bone filler which enables fusion with newly grown bone or bone substitution action quickly in a natural manner, without scattering, when filled in a bone loss portion and a process of production of the same.
In accordance with the present invention, there is provided a process for producing ceramics by dropping starting ceramics into a low temperature medium, followed by freeze drying and, then sintering.
In accordance with the present invention, there is further provided composite spherical-shape ceramics having a composite layer obtained by dropping a starting material powder into a low temperature medium applying a hydrothermal treatment to the resultant spherical-shape ceramics.